When It Comes to Cancer, Just How Vulnerable Are Our Children?

By Mark Lappé

Perhaps the most tragic event in the life of a parent is the death of a child. When that death is from cancer, parents are often haunted by the belief that it was something they had done - or not done - that put their child in harm's way. The reality of course is often much less certain outside our ability to know. Others are deeply embedded in our genetic legacy.

Many childhood cancers like the special eye cancer called retinoblastoma are primarily hereditary in origin. In fact, an old adage taught to pathology students is that if a cancer occurs before adolescence, look to the genes. But a growing wave of childhood cancers, particularly of the bone marrow and brain, are likely to have its origins in something else - something in the environment.

As the toxicologist charged with figuring out the "cause" of the notorious Woburn, Massachusetts cancer cluster (made famous in the film A Civil Action starring John Travolta as an impassioned attorney, Jan Schlichtman), I was impressed by two factors. The first was the unshakable conviction of Anne Anderson, then several of her neighbors ,that there were simply too many cases of childhood leukemia in their neighborhood to be explained by choice. Now, epidemiologists are the first to point out the error of seeing cancer clusters when they are simply random bunches of otherwise rare events, predictable from the so-called Poisson probability curve. In the Woburn case, it took 10 years before researchers at the Harvard School of Public Health concluded that the 16 or so childhood cancers found in the small town were probably not an "accident" at all, and a genuinely clustered event.

The second factor involves the improbable success of the search for a possible environmental cause: within months after the Woburn Cancer Cluster became a civil lawsuit under the aegis of Schlichtman's law firm, the toxicology team found the instinct of the parents to look for contaminated water-bore fruit. By today's standards, Woburn drinking water was in fact heavily contaminated by hundreds of parts per billion of two solvents, trichloroethylene and perchloroethylene. But the lynch pin in the probable cause argument came about in a strange way, almost all of the parents of the affected children drew their water from two wells on maps that were separated from the major industrial operation in town, the Riley Tannery, by the Aberjona river. A brilliant hydrologist connected the solvents used on the Riley Tannery (a division of Beatrice Foods Company) to the wells through an underground aquifer that ran under the river by doing an ingenious"draw-down" test whereby wells on one side of the river were heavily pumped to see if levels in the distant well on the other side would fall. They did. A second source of solvent contamination was W.R. Grace which was even closer to the affected wells.

But from a toxicological view, the most interesting facts were that every mother who bore a child that subsequently developed leukemia, drank and washed with water from the two wells throughout their pregnancy. And most compelling, tests of the immune systems of the affected families and their neighbors - compared to a suitable group of controls - revealed disturbances in the ability of the individuals' cells to recognize foreign antigens. This apparent defect may or may not have been directly caused by the solvent - but the link appeared inescapable: families with cancer-ridden children were families with sick immune systems.

My own work had serendipitously prepared me to think about the Woburn case. As a graduate student in experimental pathology, I had given newborn mice tiny amounts (about a milligram or 1/1000 gram) of a carcinogen called urethane within the first day after their delivery. (At this stage, the mice are about the same developmental stage as a 7-8 month human fetus) The amount of carcinogen, gave the baby mice even when adjusted for their small body weight would hardly have been sufficient to cause cancer in an adult animal. I followed the growth of the tiny animals and their sham-injected littermates through their adulthood. Along the way, I measured their immune system's strength by giving them skin grafts of foreign tissue. I then ranked the animals according to their immune scores. Those with the lowest scores - the ones that took the longest to recognize and reject the grafts - were ranked against the mice that had the strongest responses. The low scores of the mice that received carcinogen treatments (as opposed to the untreated controls) showed that long before any tumors were visible, the carcinogen had depressed the treated animals immune systems. Most critically, the mice with the greatest depression had the greatest number of tumors.

These results suggested three things that other researchers have since confirmed: that the immune system is important in keeping cancer at bay; that chemicals that cause cancer can interfere with the normal development of immune strength; and, that very early exposure to carcinogens can produce dramatic and unexpected names of cancer in adolescence or young adulthood.

The relevance to the Woburn families was striking, even if only by analogy. Each of the Woburn residents had been exposed to chemicals that could depress their immune systems. And each affected child had been exposed during pregnancy to an intrauterine dose (as well as post natal doses from drinking water) that could have started the cancer process. . Ironically, virtually no scientists other than the team put together for the lawsuit saw these connections as relevant. And the defense, representing Beatrice Foods and W.R. Grace, had no trouble finding scientists who thought our thinking was ridiculous and unscientific.

With hindsight, I think the Woburn team was on to something important about the linkage between young age of exposure and vulnerability to cancer. But at the time these events transpired, in the mid-1980s, few scientists had yet formulated their thinking about how to use data about cancer in animals to predict cancer in humans much less children, a connection currently under intense review. Only in the last year has the EPA issued draft guidance about adjusting cancer risk estimates to account for this increased vulnerability of children to environmental carcinogens.

The Woburn events all transpired before the Environmental Protection Agency had issued their first Guidelines for Carcinogen Risk Assessment in 1986. These guidelines put forward procedures and principles for scientists to use in assessing the public's risk associated with environmental chemicals. In 1996, the EPA published its formal proposal for cancer risk guidelines, and again in 1999 invited public review of its revised Guidelines.

On March 3, 2003, the EPA published its "Draft Final Guidelines for Carcinogen Risk Assessment" open for public comment through May 1, 2003. These latest revisions are designed to incorporate the most recent scientific thinking about the importance of different mechanisms that might produce cancer, and in particular invite comments about the importance of understanding and appreciating "susceptible populations and life stages, in determining cancer risk. This latter issue is treated separately in an EPA supplemental guidance document that describes possible approaches for figuring out the risks from early life exposure to potential carcinogens. The new EPA calculations indicate children under the age of 2 are 10 times , and children from 2-15 years are three times more susceptible to chemical carcinogenesis than are adults.

So, twenty years after Woburn, the EPA is finally looking at the possibility that children-and fetuses-may be especially susceptible to cancer-causing insults. In fact, an entire neglected field of research called "Perinatal Carcinogenesis" has now been re-opened. This field was once almost the exclusive province of Eastern European and Russian researchers. Perhaps surprisingly, given the resurgence of interest in susceptibility of the fetus, my contemporaries thought this new field to be too fluid and uncertain to lend itself to scientific analysis. After all, estimating the actual dose a developing embryo received from any chemical in its mother's diet or environment was a daunting challenge. Not only did you have to contend with the questions of trans-placental transfer of chemicals, but also how much (or little) would first be processed by the mother's detoxifying system - and then how much would be processed by the still immature fetus's systems was largely a matter of conjecture. Another key variable is the high rate of cell division in the developing fetus which puts replicating cellular DNA at risk for greater genetic damage than the more often quiescent double-strands in an adult. This factor alone probably explains a considerable amount of the intra-uterine cancer produced by chemicals exposed via the mother. Some chemicals, like the notorious diethylstilbestrol (DES), clearly traverse the placental "barrier" intact, and can cause enough anatomic damage to lead to cancer in subsequent generations (daughters and sons) of exposed mothers.

Whatever the eventual outcome of EPA's belated methods that are finally for assessing the enhanced childhood and intrauterine risk from environmental carcinogens, we can hope the resulting warnings about heightened risks during pregnancy and early life will avert many more tragedies like those that afflicted the families in Woburn, Massachusetts a quarter of a century ago.